Sustained release injectable therapeutic formulations using aprotic polar solvents

Abstract

The present invention concerns the use of aprotic polar solvents, water, and an ionization stabilizing agent to prepare stable therapeutic formulations, particularly sustained release formulations, of a variety of active pharmaceutical ingredients (APIs), such as, e.g., levothyroxine. In particular, the invention concerns the use of aprotic polar solvents and at least one ionization stabilizing agent to prepare stable therapeutic formulations of a variety of APIs by dissolving at least one API in an aprotic polar solvent system to produce a stable sustained release therapeutic formulation useful in treating, preventing and/or diagnosing diseases or physical disorders in humans and veterinary animals. The invention also provides methods of manufacturing such formulations.

1 . A storage stable sustained release therapeutic formulation comprising:
 (a) at least one therapeutic agent;   (b) at least one ionization stabilizing excipient; and   (c) an aprotic polar solvent system,
 wherein said at least one therapeutic agent is poorly soluble in an aqueous environment but is readily soluble in said aprotic polar solvent system, 
 wherein said formulation is storage stable for at least six months at 2° C.-8° C., 
 and wherein said formulation, when administered to a patient, results in the presence of therapeutic levels of the at least one therapeutic agent in the blood of said patient for an extended period of time relative to an immediate release formulation comprising said at least one therapeutic agent. 
   
     
     
         2 . The formulation of  claim 1 , wherein the therapeutic agent is selected from the group consisting of levothyroxine or a salt thereof, a benzodiazepine, and tamsulosin. 
     
     
         3 . The formulation of  claim 2 , wherein the therapeutic agent is levothyroxine free acid or levothyroxine sodium. 
     
     
         4 . The formulation of  claim 2 , wherein said benzodiazepine is diazepam. 
     
     
         5 . The formulation of  claim 1 , wherein the aprotic polar solvent system comprises or is dimethyl sulfoxide (DMSO). 
     
     
         6 . The formulation of  claim 1 , wherein the ionization stabilizing excipient is a mineral acid, selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. 
     
     
         7 . (canceled) 
     
     
         8 . The formulation of  claim 6 , wherein the mineral acid is sulfuric acid. 
     
     
         9 . The formulation of  claim 6 , wherein said mineral acid is present in said formulation at a molar concentration ratio of between 2:1 and 3:1 relative to the concentration of said therapeutic agent in said formulation. 
     
     
         10 . The formulation of  claim 9 , wherein said mineral acid is present in said formulation at a molar concentration ratio of about 2.5:1 relative to the concentration of said therapeutic agent in said formulation. 
     
     
         11 . The formulation of  claim 3 , wherein said formulation comprises levothyroxine sodium at a concentration of from about 5 mg/mL and sulfuric acid at a concentration of from about 13 mM to about 15 mM. 
     
     
         12 . The formulation of  claim 3 , wherein said formulation comprises levothyroxine sodium at a concentration of from about 10 mg/mL and sulfuric acid at a concentration of from about 26 mM to about 28 mM. 
     
     
         13 . The formulation of  claim 1 , further comprising one or more additional pharmaceutically acceptable excipients, selected from the group consisting of a sugar, a sugar alcohol, a preservative, and a polymer. 
     
     
         14 . (canceled) 
     
     
         15 . The formulation of  claim 13 , wherein the sugar is trehalose or a salt or hydrate thereof. 
     
     
         16 . The formulation of  claim 15 , wherein the sugar is trehalose dihydrate. 
     
     
         17 . The formulation of  claim 13 , wherein the sugar alcohol is mannitol. 
     
     
         18 . The formulation of  claim 13 , wherein the preservative is a benzyl alcohol. 
     
     
         19 . The formulation of  claim 13 , wherein the polymer is a poly(lactic-co-glycolic acid) (PLGA), wherein said PLGA is an ester-terminated PLGA or an acid-terminated PLGA. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating or preventing a disease or disorder in a human or veterinary animal, said method comprising introducing a therapeutically effective amount of the formulation of  claim 1  into a human or veterinary animal in need thereof, monitoring the levels in the plasma of said human or veterinary animal over time, and repeating the introduction of said formulation into said subject as needed to treat or prevent said disease or disorder in said human or veterinary animal. 
     
     
         22 . The method of  claim 21 , wherein the formulation is introduced into said human or veterinary animal via parenteral administration. 
     
     
         23 . The method of  claim 21 , wherein said parenteral administration is via injection or infusion. 
     
     
         24 . The method of  claim 23 , wherein said injection is a subcutaneous, intradermal, or intramuscular injection. 
     
     
         25 . The method of  claim 23 , wherein said injection is a subcutaneous injection. 
     
     
         26 . The method of  claim 23 , wherein said infusion is accomplished by pump infusion, wherein said pump infusion comprises continuous or bolus pump infusion, or a combination thereof. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 21 , wherein the therapeutic agent is selected from the group consisting of levothyroxine or a salt thereof, a benzodiazepine, and tamsulosin. 
     
     
         29 . The method of  claim 28 , wherein said therapeutic agent is levothyroxine free acid or levothyroxine sodium. 
     
     
         30 . The method of  claim 29 , wherein said disease or disorder is hypothyroidism or a disease or disorder associated with or characterized by hypothyroidism. 
     
     
         31 . The method of  claim 30 , wherein said disease or disorder associated with or characterized by hypothyroidism is thyroiditis, Hashimoto's Disease, myxedema or myxedema coma/crisis. 
     
     
         32 . The method of  claim 28 , wherein said therapeutic agent is a benzodiazepine. 
     
     
         33 . The method of  claim 32 , wherein said benzodiazepine is diazepam. 
     
     
         34 . The method of  claim 32 , wherein said disease or disorder is anxiety, muscle spasms, or seizures. 
     
     
         35 . The method of  claim 28 , wherein said therapeutic agent is tamsulosin. 
     
     
         36 . The method of  claim 35 , wherein said disease or disorder is benign prostatic hyperplasia or kidney stones. 
     
     
         37 . A method of producing a storage stable sustained release therapeutic formulation of at least one therapeutic agent, said method comprising mixing at least one ionization stabilizing excipient, an aprotic polar solvent system, and at least one therapeutic agent that is poorly soluble in an aqueous environment but that is readily soluble in said aprotic polar solvent system, thereby forming a storage stable sustained release therapeutic formulation that, when administered to a human or veterinary animal, results in the presence of therapeutic levels of the at least one therapeutic agent in the blood of said human or veterinary animal for an extended period of time relative to an immediate release formulation comprising said at least one therapeutic agent. 
     
     
         38 . The method of  claim 37 , wherein the therapeutic agent is selected from the group consisting of levothyroxine or a salt thereof, a benzodiazepine, and tamsulosin. 
     
     
         39 . The method of  claim 38 , wherein the therapeutic agent is levothyroxine free acid or levothyroxine sodium. 
     
     
         40 . The method of  claim 38 , wherein said benzodiazepine is diazepam. 
     
     
         41 . The method of  claim 37 , wherein the aprotic polar solvent system comprises or is dimethyl sulfoxide (DMSO). 
     
     
         42 . The method of  claim 37 , wherein the ionization stabilizing excipient is a mineral acid, selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 42 , wherein the mineral acid is sulfuric acid. 
     
     
         45 . The method of  claim 42 , wherein said mineral acid is present in said formulation at a molar concentration ratio of between 2:1 and 3:1 relative to the concentration of said therapeutic agent in said formulation. 
     
     
         46 . The method of  claim 45 , wherein said mineral acid is present in said formulation at a molar concentration ratio of about 2.5:1 relative to the concentration of said therapeutic agent in said formulation. 
     
     
         47 . The method of  claim 39 , wherein said formulation comprises levothyroxine sodium at a concentration of from about 5 mg/mL and sulfuric acid at a concentration of from about 13 mM to about 15 mM. 
     
     
         48 . The method of  claim 39 , wherein said formulation comprises levothyroxine sodium at a concentration of from about 10 mg/mL and sulfuric acid at a concentration of from about 26 mM to about 28 mM. 
     
     
         49 . The method of  claim 37 , further comprising one or more additional pharmaceutically acceptable excipients, selected from the group consisting of a sugar, a sugar alcohol, a preservative, and a polymer. 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 49 , wherein the sugar is trehalose or a salt or hydrate thereof. 
     
     
         52 . The method of  claim 51 , wherein the sugar is trehalose dihydrate. 
     
     
         53 . The method of  claim 49 , wherein the sugar alcohol is mannitol. 
     
     
         54 . The method of  claim 49 , wherein the preservative is a benzyl alcohol. 
     
     
         55 . The method of  claim 49  wherein the polymer is a poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA is an ester-terminated PLGA or an acid-terminated PLGA. 
     
     
         56 . (canceled)